Carfilzomib, Pomalidomide and Dexamethasone (KPd) in Patients with First Progression of Multiple Myeloma Refractory to Bortezomib and Lenalidomide. Final Report of the EMN011/HOVON114 Trial

Introduction and background

Treatment of newly diagnosed Multiple Myeloma (MM) with Bortezomib, Imid and Dexamethasone followed by high-dose therapy and Lenalidomide maintenance has become standard with an estimated progression-free survival (PFS) of 5 years. In the EMN02 collaborative trial VCD induction (Bortezomib, Cyclophosphamide, Dexamethasone) followed by HDM/ASCT or VMP (Bortezomib, Melphalan, Prednisone), followed by VRD consolidation and Lenalidomide maintenance until progression resulted in a median PFS of 57.5 months from start of maintenance at a median follow-up of 73 months (Cavo et al, Lancet Haematol 2020; Sonneveld et al, J Clin Oncol 2021). Patients with progressive disease during Lenalidomide maintenance are defined as double refractory and have limited options for treatment. The present Phase 2 trial was designed to evaluate a salvage treatment of next generation proteasome inhibition and IMId, i.e., Carfilzomib, continuous Pomalidomide and Dexamethasone (KPd) for patients who developed a first progression after treatment in EMN02 The primary endpoint was progression-free survival (PFS). This trial is registered as NTR5349 and EudraCT 2013-003265-34.

Methods

Patients were eligible if they had PD according to IMWG criteria during treatment in EMN02. Treatment consisted of 8 cycles of KPd, i.e. Carfilzomib (20/36mg/m ², days 1,2,8,9,15,16) with Pomalidomide (4 mg days 1-21) and Dexamethasone (20mg days 1,2,8,9,15,16). In patients who had not previously received HDM/ASCT, HDM(200 mg/m ²) was administered followed by autologous transplantation with stem cells previously harvested.. Patients who achieved stable disease or better were randomized to receive Pomalidomide 4mg (21/28 days) with or without Dexamethasone 40mg (days 1, 8, 15, 22) in 28 days cycles until progression.

Results

At the time of the final analysis 112 patients were registered of whom 1 was ineligible. 59% had received prior HDM/ASCT and 41% VMP. Prior best responses in the EMN02 trial were 39% ³CR , 81% ≥VGPR, 96% ≥PR. The median duration of maintenance in EMN02 had been 33 months and median PFS from start of maintenance 59 months. At inclusion adverse risk factors were available in 92/111 patients, ie R-ISS II or III 62%, del17p 14%, t(14;16) 1%, t(4;14) 20%, amp1q 40%. One hundred (90%) of patients had progressed during or within 6 months after discontinuation of Lenalidomide maintenance.

86 (77%) patients completed 8 cycles of KPd, of whom 69(62%) without dose reduction and received continuous Pomalidomide with Dexamethasone (38%) or without (40%). The median time to discontinuation of Pomalidomide w/o Dexamethasone was 17 months (18 vs 15 months, n.s.). In addition, thirty-three of 42 (79%) eligible patients received their first HDM plus ASCT. Time to first response was 2 months. Best response on protocol was 37% ≥CR, 75% ≥VGPR, 92% ≥PR, respectively. At a median follow-up of 40 months (range 9-66 months) median PFS from registration was 26 months. PFS from randomization was 27 months (Pom/Dex) and 18 months (Pom) respectively (HR 0.68, 95%CI 0.41-1.13, p=0.14). 70 (63%) of patients are alive and in follow-up. With Cox regression analysis predefined risk factors including high-risk cytogenetics (HR 1.36, 95%CI 0.80-2.41), prior HDM/ASCT (HR 1.25, 95%CI 0.78-2.01) and duration of prior maintenance >36 months (HR 3.56, 95%CI 1.42-8.96) were not significant. Median overall survival (OS) was 67 months. KPd-emerging grade 3 and 4 adverse events included hematologic (41%), cardiovascular (6%), respiratory (3%), infections (17%) and neuropathy (2%). There were 6 fatal SAEs not related to progression (1 patient cardiovascular).

Discussion

This Phase 2 trial demonstrates that KPd followed by Pomalidomide until progression is an effective and safe triple drug regimen in second-line for patients who are refractory to Lenalidomide. The benefit is observed across subgroups of risk factors. A 92% overall response and 26 months PFS is clinically relevant in this population and compares favourably to Pom/Vd. Using this regimen HDM/ASCT could be performed in the majority of patients.

Acknowledgements

This trial was conducted as an investigator sponsored trial by HOVON and the European Myeloma Network EMN and supported by a grant from the Dutch Cancer Foundation and by independent grants and drug supply from Amgen and BMS/Celgene.